Monday, 3 February 2014

Specifically turning off the immune response

Hunter Z, McCarthy DP, Yap WT, Harp CT, Getts DR, Shea LD, Miller SD. A Biodegradable Nanoparticle Platform for the Induction of Antigen-Specific Immune Tolerance for Treatment of Autoimmune Disease. ACS Nano. 2014 Feb. [Epub ahead of print]

Targeted immune tolerance is a coveted therapy for the treatment of a variety of autoimmune diseases, as current treatment options often involve non-specific immunosuppression. Intravenous (i.v.) infusion of apoptotic syngeneic splenocytes linked with peptide or protein autoantigens using ethylene carbodiimide (ECDI) has been demonstrated to be an effective method for inducing peripheral, antigen-specific tolerance for treatment of autoimmune disease. Here, we show the ability of biodegradable poly(lactic-co-glycolic acid) (PLG) nanoparticles to function as a safe, cost-effective and highly efficient alternative to cellular carriers for the induction of antigen-specific T cell tolerance. We describe the formulation of tolerogenic PLG particles and demonstrate that administration of myelin antigen-coupled particles both prevented and treated relapsing-remitting experimental autoimmune encephalomyelitis (R-EAE), a CD4 T cell-mediated mouse model of multiple sclerosis (MS). PLG particles made on-site with surfactant modifications surpass the efficacy of commercially available particles in their ability to couple peptide and to prevent disease induction. Most importantly, myelin-antigen coupled PLG nanoparticles are able to significantly ameliorate ongoing disease and subsequent relapses when administered at onset or at peak of acute disease, and minimize epitope spreading when administered during disease remission. Therapeutic treatment results in significantly reduced CNS infiltration of encephalitogenic Th1 (IFN-γ) and Th17 (IL-17a) cells as well as inflammatory monocytes/macrophages. Together, these data describe a platform for antigen display that is safe, low-cost and highly effective at inducing antigen-specific T cell tolerance. The development of such a platform carries broad implications for the treatment of a variety of immune-mediated diseases.

Immune tolerance in the process of reducing the certains pecific immune responses that cause the disease, whilst leaving the rest intact so that the immune system can fight infection. 

The original idea that you could couple myelin antigens to cell carriers was developed in EAE and it now has been tried in a phase I study in humans.They fixed peptides to cells and if they used high number of myelin peptide cells it reduced myelin reactive T cell responses, they say safety (although some relapses appeared to occur within days of the treatments). Each person would have their own cells coated in peptides (Thankfully there were no strokes, which could be a risk if cell clumping occurs when they are cross linked with the EDCI fixative) but the approach is not very pharmaceutical for mass production. However, MD2 showed in 2005 that you don't need to use cells as carriers and you could use beads.

Following on from the idea of MD2 that you can attach antigens to beads as a way if switching off the immune response it was subsequently shown that you could use biodegradable micro beads (500nm diameter) http://multiple-sclerosis-research.blogspot.co.uk /2012/11/research-antigen-coated-beads-new-old.html. In this newer study they used much smaller beads called nano beads and they work in EAE too. Some people will say use peptides without the beads and they will work too, which could indeed the case as it has already been done. However, if used after the first attack, peptides can make disease worse. The idea of the beads is to stop this potential side effect. 

This development allows one to commercialise the approach such this could be developed for a treatment in MS.

If it were to be developed would it be "low cost"...I doubt it as MS drugs cost are not proportional to their manufacture cost. But if the approach is to be developed in my humble opinion they will probably miss an opportunity if they do not transiently deplete cells first before applying the tolerance. We have done this type of treatment a lot  and a lot later than after the onset of the first attack and it just doesn't work very well, or as well as it could without a deletion step.

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